3-Substituted-as-triazino(5,6-c) quinoline derivatives

ABSTRACT

New 3-substituted as-triazino(5,6-c)quinoline derivatives of the general formula (I)   wherein R represents hydrogen, a C1-4 alkyl group, an aralkyl group containing 1 to 4 carbon atoms in the alkyl chain, pyridyl, or a phenyl group optionally substituted with a halogen, nitro, hydroxy or amino group, R1 and R2 each represent hydrogen, or form together a chemical bond ARE PREPARED AS FOLLOWS: 4-CHLORO-3-NITROQUINOLINE IS REACTED WITH A CARBOXYLIC HYDAZIDE OF THE GENERAL FORMULA (II)

United States Patent 1 Berenyi nee Poldermann et al.

1211 Appl. No.: 357,722

[30] Foreign Application Priority Data May 5. 1972 Hungary EE2022 [52] U.S. Cl 260/248 AS, 424/249, 260/287 R [51] Int. Cl C07d 57/34 [58] Field of Search 260/248 AS I [56] References Cited UNITED STATES PATENTS 3,597,427 8/l97l Lewis 260/248 Primary Examiner-John M. Ford Attorney, Agent, or FirmYoung & Thompson [57] ABSTRACT New B-substituted as-triazino[5,6-clquinoline derivatives of the general formula (I) 2 n R1-N wherein R represents hydrogen, a C alkyl group, an aralkyl group containing 1 to 4 carbon atoms in the alkyl chain, pyridyl, or a phenyl group optionallysubstituted with a halogen, nitro, hydroxy or Mar, 25, 1975 amino group, R, and R each represent hydrogen. or form together a chemical bond are prepared as follows: 4-chloro-3-nitroquinoline is reacted with a carhoxylic hydazide oi the general formula (ll) RCONHNH or 4-hydrazino-3-nitroquinoline is reacted with a car boxylic halide of the general formula (lla)" RCOX (llu) wherein X represents a halogen atom-, the thus-obtained 4-acylhydrazino-3-nitroquinoline of the general formula (Ill) CO-R (III) is reduced, the thus-obtained 4-acylhydrazino-3- aminoqui-noline of the general formula (IV) is subjected to ring closure in an acidic inedium, and the formed l,2-dihydro-as-triazinol5,6-c]quinoline is isolated in the form of its acid addition salt, or oxidized into the corresponding as-triazino[5,6- clquinoline, if desired.

The new compounds of the general formula (I) possess anti-inflammatory and antimicrobial activities.

1 Claim, N0 Drawings 3-SUBSTITUTED-AS-TRIAZINO(5 ,6-C) QUINOLINE DERIVATIVES wherein R represents hydrogen, C alkyl group, and aralkyl group containing 1 to 4 carbon atoms in the alkyl chain, pyridyl, or a phenyl group optionally substituted with a halogen, nitro, hydroxy or amino group,

R and R each represent hydrogen, or form together a chemical bond. These compounds are of basic character and form addition salts with acids. The scope of the invention encompasses also the acid addition salts of the new quinoline derivatives, as well as the processes for the preparation of such salts.

The new compounds of the general formula (I) can be prepared as follows: 4-chloro-3-nitroquinoline is reacted with a carboxylic hydrazide of the general formula (ll) or 4-hydrazino-3-nitroquinoline is reacted with a carboxylic halide of the general formulallla) in the above formulae R has the same meanings as defined above and X represents a halogen atom the thus-obtained 4-acylhydrazino-3-nitroquinoline of the general formula (lll) wherein R has the same meanings as defined above m is reduced, the thus-obtained 4-acylhydrazino-3- aminoquinoline of the general formula (IV) wherein R has the same meanings as defined above is subjected to ring closure in an acidic medium, and the formed l,2-dihydro-as-triazinol5,6-c]quinoline is isolated in the form of its acid addition salt, or oxidized into the corresponding B-substituted-as-triazino[5,6- c]quinoline, if desired.

4-Chloro-3-nitroquinoline can be reacted with the respective carboxylic hydrazide in equimolar amounts in an alcoholic medium to yield the hydrochloride of the respective 4-acylhydrazino-3-nitroquinoline. These hydrochlorides hydrolyze very easily. The carboxylic hydrazide, however, can also be used in excessive amounts to yield the free base of the general formula (111). Either the free bases of the general formula (lll), or their acid addition salts can be converted into the re spective 3-aminoquinoline derivatives with good yields by treating them with hydrogen in a solvent medium in the presence of a hydrogenating catalyst.

The ring closure of the 3-amino-compounds is ac complished upon the action of an acid, such ashydrochloric, polyphosphoric, etc. acid. When carrying out the ring closure in ethanolic hydrochloric acid, the respective 3-substituted-l ,2-dihydro-as-triazino[ 5 ,6- clquinoline is obtained in the form of its hydrochloride, which generally separates from the reaction mixture. The hydrochloride of the dihydro compound can optionally be oxidized into the corresponding aromatic compound of the general formula (I). The oxidation is preferably carried out in alkaline medium in the presence of hexacyanoferrate ions.

According to the pharmacological examinations the compounds of the general formula (I) possess antiinflammatory and antimicrobial activities. The antiinflammatory activity of the new compounds was investigated on rats by the carrageenin-oedema test, using the method of Winter et al. (J. Pharmacol. Exp. Ther. 141, 369 /l963/). Male rats weighing to g. were used as test animals. 0.1 ml. doses of carrageeninsuspension were injected subcutaneously into the hind paws of the animals, and the thus-provoked oedema was measured by plethysmometer. The compound to be tested were administered orally in the doses as indi cated in Table l. The percentage inhibition was calculated by comparing the measures of oedema of the tested animals to that of the controls.

The results of the above test are summarized in Table TABLE l-Continued Dosis lnh ibition LD Tested compound mg./kg. mgJkg.

as-triazino I 5 ,6-c lquinoline 200.00 38.6 3000 lbenzyl-as-triazino- [5,6-C]quinline 200.00 32.6 3000 3-( 4 -pyridyl Hts-triazino[5,6-c]quinoline 20.0 12.9

40.0 34.1 1000 80.0 56.2 as-triazinol 5 ,6-c ]quinoline 0.87 24.3

1.75 32.8 90 3.5 43.5 Aspirin 180.00 39.0 1500 Phenylbutazon 30.0 33.0 1000 90.0 45.0 lndomethacine 3.0 30.0 24.3

The compounds of the invention can be transformed to pharmaceutical products by admixing them with carriers and/or auxiliary agents usable in the pharamaceutical industry. The pharmaceutical preparations may contain other biologically active and/or synergistic agents besides the compound of the general formula (l).

The invention is elucidated in detail by the aid of the following non-limiting Examples.

EXAMPLE 1 1-B-Benzhydrazino-3-nitroquinoline 13.6 g. (0.1 mol.) of benzoic hydrazide are dissolved in 200 ml. of ethanol, and 20.8 g. (0.1 mol.) of 4- chloro-3-nitroquino1ine are added to the stirred solution at a temperature of to 40 C. A dark red suspension is obtained, which gradually turns yellow, After 3 hours of stirring the separated light yellow, crystalline substance is filtered off and dried. 31.6 g. (92 of 4-B-benzhydrazino-3-nitroquinoline hydrochloride are obtained; m.p.: 244-246 C.

The obtained salt is suspended in tenfold amount of water, and the base is liberated by adding equimolar amouiit of Na- CO to the solution. The dark purple 4- B-benzhytlrazino-3-nitroquinoline base melts at 202203 C after recrystallization from nitrobenzene.

EXA M PLE 2 4-B-Phenylhydrazino3-nitroquino1ine 30.0 g. (0.2 mol.) of phenylacetic hydrazide are dissolved in tenfold amount of ethanol, and 20.8 g. (0.1 mol.) of 4-ch1oro-3-nitroquino1ine are added to the stirred solution. The mixture is stirred for 2 hours at room temperature, and the separated product is filtered off. 30.6 g. (96 of 4-B-pheny1acetylhydrazino-3-nitroquino1ine are obtained; m.p.: 199-200 C.

The following compounds are prepared as described in Examples 1 or 2, respectively:

4-i-formylhydrazino-3-nitroquinoline; m.p.: 190-191 4- B acetylhydrazino-3-nitroquinoline; m.p.: 194195 4-3 -nicotinoylhydrazino-3-nitroquinoline; m.p.: 243 4-B s a1icylic A hydrazino-3-nitroquinoline; m.p.:

4-,8-(p-nitrobenzhydrazino)-3-nitroquinoline;

4-8-(3, 4, 5-trimethoxybenzhydrazino)-3 nitroquinoline, m.p.: 213215 C,

4-,8-( 3 4-dimethoxyphenacetylhydrazino)-3 nitroquinoline, m.p.: 168-170 C,

4-,B-(p-bromobenzhydrazino)-3nitroquinoline;

EXAMPLE 3 2.04 g. (0.01 mol.) of 4-hydrazino-3-nitroquinoline are dissolved in 20 ml. of pyridine, and 1.4 (0.01 mol.) of benzoylchloride are added dropwise to the stirred solution. The reaction mixture is boiled for one hour, thereafter it is cooled and poured onto water. 4- B-Benzhydrazino-3-nitroquin0line, a product identical to that prepared in Example 1, is obtained.

EXAMPLE 4 3-Amino-4-,B-benzhydrazinoquinoline 6.2 g. (0.02 mol.) of 4-B-benzhydrazino-3- nitroquinoline are hydrogenated in an ethanolic medium, in the presence of palladium catalyst. When the hydrogen uptake ceases, the mixture is filtered. and the filtrate is evaporated. 4.6 g. (83 of 3-amino4-B- benzhydrazinoquinoline are obtained; m.p.: 192-193 C.

EXAMPLE 5 3-Phenyl-1,2-dihydro-as-triazino[5 ,6-c lquinoline hydrochloride 5.6 g. (0.02 mol.) of 3-amino-4fi- EXAMPLE 6 6.0 g. 0.02 mol.) of 3-phenyl-1,2-dihydro-astriazino[5,6-c]quinoline hydrochloride are added to the solution 0f13.2 g. (0.04 mol.) of K Fe(CN) in m1. of water at 0 C. Prior to addition the pH ofthe solution is adjusted to 9 with concentrated ammonium hydroxide. The reaction mixture is stirred at 0 "C for 3 hours, thereafter the separated substance is filtered off. 5.0 g. (97 of 3-phenyl-as-triazonl5,6-c]quinoline are obtained; m.p.: 203204 "C (after recrystallization from a mixture of ethanol and chloroform).

hy- I 

1. A 3-SUBSTITUTED AS-TRIAZINO(5,6-C)QUINOLINE DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 